Breakthrough in Treatment of Triple Negative Disease: A MUST READ!!!

NEW Targeted Drug Seeks and Destroys TNBC...
This could be big. Breast cancer is not one disease as we all know. Triple Negative Breast Cancer has been on the back burner in terms of new therapies, until now. PARP treatment is changing the future of metastatic TNBC patients. Now, a new, targeted therapy has identified a sub-type of TNBC tumors...

New Subtype of Breast Cancer Responds to Targeted Drug
ScienceDaily (Mar. 2, 2010) — A newly identified cancer biomarker could define a new subtype of breast cancer as well as offer a potential way to treat it, say researchers at Washington University School of Medicine in St. Louis.

Their findings will be published in the March 1 online early edition issue of the Proceedings of the National Academy of Sciences.

The research could further refine what recent breast cancer research has concluded: that breast cancer is not one disease, but many. So far, research has firmly established that at least five subtypes of breast cancer exist, each having distinct biological features, clinical outcomes and responses to traditional therapies.

The biomarker identified by the Washington University researchers is found frequently in breast cancers and especially in those that have poorer outcomes. It stems from overactivation of a gene called LRP6 (low-density lipoprotein receptor-related protein 6), which stimulates an important cell-growth signaling pathway. LRP6 can be inhibited by a protein discovered in the same laboratory, which could become an effective drug against the breast cancer type, the researchers say.

"We found increased expression of the LRP6 gene in about a quarter of breast cancer specimens we examined, and we think LRP6 overexpression could be a marker for a new class of breast cancer," says Guojun Bu, Ph.D., professor of pediatrics and of cell biology and physiology. "In addition, we found that this biomarker is often associated with breast cancers that are either harder to treat or more likely to recur. We already have an agent that seems to be effective against LRP6-overexpressing tumors, which could someday become a therapy for tumors that right now have few treatment options."
The research was conducted primarily by Chia-Chen Liu, a graduate student in the Bu lab, who is a fellow in the Cancer Biology Pathway Program at the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital.

The researchers' analysis of human breast cancer tissue samples found significant increases in LRP6 levels in 20 percent to 36 percent of the tumors. LRP6 was increased more frequently in ER (estrogen receptor)-negative or HER2 (human epidermal growth factor receptor 2)-negative samples. LRP6 was also increased more frequently in so-called triple-negative breast tumor samples, which test negative for ER, HER2 and PR (progesterone receptor).

In general, patients who have triple-negative breast cancers have an increased risk of disease recurrence after initial treatment and a poorer prognosis. Furthermore, although ER-positive and HER2-positive tumors can be targeted with specific therapies, ER-negative and HER2-negative tumors cannot. So it appears that LRP6 overexpression is often associated with tumors that are currently difficult to treat, says Bu.

Research in the lab had earlier discovered a protein that binds to and inhibits LRP6. This study showed that the protein, called Mesd (mesoderm development), was able to slow the growth of breast cancer cells in the laboratory and to inhibit mammary tumor growth in laboratory mice.

Importantly, mice treated with Mesd did not experience any of the known side effects, such as bone lesions, skin disorders or intestinal malfunctions, associated with inhibition of this growth pathway.
"Our work introduces Mesd as a promising antitumor agent that might be further developed for breast cancer therapy," Bu says. "It would be analogous to such successful breast cancer therapies as Herceptin (trastuzumab), which specifically targets HER2-positive breast cancer."

The researchers also found that a small segment of Mesd has the same effect as the larger molecule. This segment, or peptide, is more stable than the whole protein molecule and can be easily synthesized.

The researchers have patented the protein and the peptide through the university's Office of Technology Management. Recently, Raptor Pharmaceutical Corp. licensed Mesd from the university to develop it for clinical use.

Funding from the National Institutes of Health and the Siteman Cancer Center supported this research.

Got Hope? TNBC patients do now!

The Reviews Are in:
Blockbuster drug known as PARP = A future of hope

"I believe that in the next two to three years, PARP inhibitors will do for triple-negative breast cancer what trastuzumab [Herceptin] did for HER2 breast cancer." Jenny Chang, Baylor

"This development may have the potential to change patient survival . . . and appears to potentially change the natural history of at least a subclass of metastatic breast cancer [TNBC]" Clifford Hudis, MSK

“When you go home, be excited. Be really excited about this. Tell your patients there is reason to be hopeful.” Eric Winer, Dana Farber

Until now, the treatment for triple negative breast cancer has been limited. The options for metastatic patients were few and far between. Until now. The first completed studies of PARP, have shown that not only does it slow progression of disease, but patients are experiencing a complete response to the drug.

The side effects of PARP are generally well tolerated and do not include hair loss.

Where once there was no hope, no magic drug for triple negative patients, PARP is proving itself to be, as Dr. Jenny Chang, of the Baylor School of Medicine said, “What Herceptin did for HER2 breast cancer.”

“Many experts have argued that it is not possible to change survival in stage IV breast cancer. Certainly now there evidence for an alternative viewpoint; that with the use of very effective drugs, we can change overall survival, and we should aim for that." Clifford Hudis, MSK

For more information, speak to your oncologist. For information on recruiting trials for PARP click the following links:

Chang C.  Interview with Neil Love.  in Conversations with Oncology  Investigators - Bridging the Gap between Research and Patient Care.  Breast Cancer Update 2009;8(6):3-6 [Track 5; with audio].

Hudis C.  Interview by L Scott Zoeller 2009 Oct 21.  Extended Survival With PARP Inhibitors Changes Expectations in Metastatic Breast Cancer.  Viewpoints.  In OncologySTAT 2009.

Carlson R.  PARP Inhibitors Show Promise Against Metastatic Triple-Negative Breast Cancer in Early Studies.  Oncol Times 2009;31(15):10-11.

Triple Negative Breast Cancer News: Genome Project

Background: Drug companies have developed an array of drugs to attack cancer and other conditions influenced by genetics, but it’s difficult to tell which patients will respond to which drugs.

What’s happening: A new study will sequence the genomes of cancer tissue from 14 breast cancer patients whose tumors have progressed despite multiple treatments.

The future: Proponents of “genomic medicine” think it will become increasingly possible to use sequencing to steer individual patients to the drugs most likely to work.

A Carlsbad biotechnology company is helping launch an unusual cancer study that may eventually lead to doctors tailoring treatments to patients’ genes. Life Technologies says the study — involving sequencing the genomes of 14 patients with a tough-to-treat form of breast cancer — is a step toward a future of “genomic medicine,” a decade after the sequencing of the first human genome.

It’s evidence of how quickly work in this area is progressing, with the $2.6 billion thatwent into the Human Genome Project reduced to $6,000 per genome on Life Technologies’ latest sequencing instrument. “This is a pretty amazing example of how far these tools of genomics are moving into direct patient applications,” said Jeffrey Trent, president of the Phoenix-based Translational Genomics Research Institute, which is workingwith Life Technologies on the project.

The company will announce the study today to coincide with the opening of a two-day conference on genomic medicine in La Jolla, at which experts will discuss the latest breakthroughs and the outlook for more advances in the field. Already, biotechnology research has created numerous drugs that target genetic problems that lead to cancer and other conditions. In the case of breast cancer, at least a dozen such drugs are on the market, said Dr. Daniel D. Von Hoff, physician-in-chief at the translational genomics institute. A big problem, however, is that it’s difficultto predict which drugs will work for a particular patient. That’s where sequencing is supposed to help.

“For those mutations for which we do have drugs, we can help the physician make more informed decisions than they’re making today,” said Linh Hoang, director of personalized medicine at Life Technologies.
The study could also help scientists identify promising areas to explore for future drugs. It’s impossible to know ahead of time whether the 14 patients have genetic patterns that current drugs address, but researchers will also look for similarities in the DNA of the 14.

“It may lead to more targets that pharmaceutical companies will want to design drugs around,” Hoang said.
The study will involve patients with what’s known as triple-negative breast cancer whose tumors have progressed despite multiple therapies. That type of cancer makes up about a fifth of breast cancer cases and doesn’t respond to common drugs, such as Herceptin. Patients will be enrolled by U.S. Oncology, a Houston-area company that specializes in cancer-treatment services, and Von Hoff said the plan is to take the first 14 people who meet the study criteria.

A spokeswoman for U.S. Oncology said the company plans to enroll patients from about a half-dozen of its sites with the highest incidences of triple-negative cases. Sites in Colorado, Oregon, Texas and Virginia have already been identified.

Tissue samples will be obtained through noninvasive surgery, Von Hoff said. Then the patients will go home to await sequencing results that should be produced within a few weeks.

The idea is to then direct them to appropriate treatment, but Von Hoff declined to predict in how many cases that will be possible. “We don’t know,” Von Hoff said. “We do know there are more and more drugs out there forpatients who have mutations.”

There have been other studies that sequenced disease tumors, most notably an ongoing government effort known as the Cancer Genome Atlas that aims to produce comprehensive genetic maps of at least 20 types of cancer.

What separates the new study is its attempt use the data to drive treatment strategies, not merely to collect information “It’s a different question,” the genomics institute’s Trent said. “This is a study about how we’re going to start to use this in a precision medicine approach.”

A big effort will go into “bioinformatic” analysis, which Von Hoff said will involve a trillion pieces of data per patient. Hoang said one project in lung cancer found 30,000 mutations.

In coming years, scientists expect the cost of sequencing to decline and the sophistication of the tools to improve to the point that sequencing becomes more viable as a diagnostic device.

Hoang said Life Technologies expects the cost of the reagent chemicals that it sells, which enable genome sequencing, to drop from $6,000 to $3,000 by the end of the year. “This is really laying the foundation for a future that may take five or 10 years to materialize,” Hoang said. “But it is truly groundbreaking.”
Thomas Kupper, The Union Tribune,

The No Surrender Breast Cancer Foundation is blessed to have Constantine Kaniklidis to report to us from the front lines of breast cancer research and treatment advances. This is one of the most exciting and hopeful breakthroughs we have ever been able to provide our readers.

For all women who have triple negative breast cancer,
this is the hope we have been waiting for.

By Constantine Kaniklidis

Major Breakthrough in the Treatment of Triple Negative Breast Cancer

  • A recent updated analysis of the original BS-201 PARP Inhibitor (PARPi) Trial continues to show an exceptional outcome benefit to the addition of the PARP inhibitor (PARPi) BSI-201 to the gemcitabine-carboplatin chemotherapy backbone, and although these are interim and not final results which could change in either direction, at this time the interim findings support the provisional conclusion that the PARP inhibitor essentially - and amazingly - doubles overall survival (OS) - not just PFS (progression-free survival), also improved, meaning reduction in the risk of recurrence - in the triple negative breast cancer population, and at this time sustains a 50% reduction in the risk of death.
    [Disclaimer: we must wait the final results  of the trial to see if these dramatic, first-ever results, are sustained at the same or reasonably comparable levels as now seen with the interim findings].

  • These rather stunning survival outcomes were furthermore accompanied by highly impressive response rates: the  overall response rate (ORR) was high, at 48% of patients achieving complete response (CR) or partial response (PR) which is  three times as high as that obtained with chemotherapy alone, and with another 14% achieving stable disease  (SD, for  6 month or greater), yielding a clinical benefit rate (CBR) of 62% (CBR = CR + PR + SD), and with no significant additional adverse effects from the addition of BSI-201 to  the chemotherapy backbone (impressive, remembering that non-toxic agents are notoriously hard to come by in oncology).

  • The accrual and progress of the trial has proceeded at extremely rapid pace, well beyond expectations, and the best estimation, based on feedback from investigators, is  that this Phase III trial given the pace, will come to completion as early as this (First) Quarter of 2010. Interview statements - but not officially posted NCI protocol data - suggests that there are just 40 patients remaining requiring trial accounting, 20 in the PARP inhibitor arm, and another 20 in the chemotherapy only arm, confirming that completion is very close, and  that a First Quarter 2010 estimate is plausible on the progress to date.

  • Finally, on the regulatory front it also appears there is accelerated progress: the PARP inhibitor BSI-201 has been granted on Fast Track Designation by the FDA, very good news for patients: FDA Fast Track means that, against standard requirements, the agency will accept initial late-stage data instead of waiting for entire Phase III clinical trial results, something that is done when (1) a  proposed agent is intended for treatment of a serious or life-threatening disease -  a status now accepted by the FDA for mTNBC (metastatic TNBC) - and (2) demonstrates the potential to address unmet needs for such a condition. Based on this status and on a review of documents filed in the FDA regulatory pipeline process, it is now estimated that  BSI-201 may actually become commercially available - and hence available to all mTNBC  patients in clinical practice without being on any clinical trial - at year's end (mid November to mid December, best estimate).

Commentary:  Missed, and New, Opportunities
My own sense of the ASCO BSI-201 PARP trial is that on the contrary that it may have  underestimated the true benefit; this perspective stems from my own TNBC review and  research which on the cumulative evidence suggests that maximal benefit of PARP inhibition is accrued when it is concurrent with a strongly 
genotoxic (DNA-damaging) regimen, and although carboplatin is genotoxic, as are all platinum agents, gemcitabine (Gemzar) is not, and I believe this represents a lost opportunity.  Indeed, I have on several  occasions advocated in this context the omission of gemcitabine (Gemzar)  altogether in the  PARP  context, in favor either of (1) a more optimal dose of carboplatin - I consider carboplatin AUC=2 as  substantially sub-optimal, and would have deployed at least AUC=6 even up to AUC=7.5, or (2) substituting another genotoxic agent  instead of gemcitabine (Gemzar), my choice being an anthracycline (preferably the pegylated liposomal Doxil or Caelyx.  Given this limitation - which in all fairness the principal investigator Joyce O'Shaughnessy has acknowledged (due to expediency, not oversight) - of the  failure to maximize the potential synergy of genotoxicity and PARP inhibition, in my mind therefore the trial's  findings are actually therefore even more impressive by extrapolation, ad I would predict that an all-genotoxic chemotherapy + PARP inhibitor (BSI-201) will achieve significantly greater outcome benefit than even doubling of survival and halving of mortality for metastatic TNBC patients.

And this is where the opportunity can be regained, in the earlier availability of BSI-201 by this year's end, since at that point clinicians are no longer constrained to conform to the trial protocol's chemotherapy regimen, and I would advocated for them to instead adopt a more
optimal all-genotoxic regimen which should translate to even more dramatic outcome gains.  I am also of the opinion for molecular and other reasons that the failure of response of the PARP inhibitor regimen for some patients may be due in part to the absence of  pure genotoxicity in the combination regimen, which therefore I am hoping innovative oncologists will recognize and overcome through appropriate DNA-damaging agent substitutions for the non-genotoxic gemcitabine (Gemzar) component, allowing more patients to be responsive to this breakthrough for metastatic TNBC disease.

Come The Revolution
Finally, remember the last time we heard of a 50% gain in breast cancer survival?  That was with the revolutionary, practice-changing (virtually overnight) findings from Dennis Slamon's trial on
trastuzumab (Herceptin) for HER2-positive disease, heralded correctly as the greatest breakthrough in breast cancer treatment since tamoxifen 30+ years ago.  I believe an optimally genotoxic PARP inhibitor therapy can do for triple negative disease what Herceptin did for HER2+ patients, and the provisional results of the  Phase III PARP Inhibitor to date appear to support and imply that contention.  

These are the kind of times that researchers like me - and dedicated and brilliant investigators, and soon also patients - live to see as their reward for their commitment.

Constantine Kaniklidis

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